Heart failure, a leading cause of hospitalization and one of the primary driving forces behind rising healthcare costs, is a complex disease that is a result of the interplay among multiple genes in combination with lifestyle and environmental factors. Previous large-scale human genome-wide association studies to identify genetic variation underlying the heart failure disease spectrum have yielded limited insights. As part of my PhD thesis, we turned to a systems genetics resource, called the Hybrid Mouse Diversity Panel, to characterize cardiac structural and functional changes under chronic isoproterenol stress over 3 weeks. We identified Myh14 as a top candidate for left ventricular mass hypertrophy. Using a genetically modified Myh14 knockout mouse line, we validated Myh14 as a novel modifier gene for left ventricular hypertrophy secondary to chronic isoproterenol stimulation. This proposal describes a five-year mentored physician-scientist training program to further define the role of Myh14 in stress-induced cardiac remodeling. We hypothesize that Myh14 is a negative regulator of hypertrophy. Based on prioritization using systems genetics and experimental findings, we have outlined a series of molecular biology, cell biology, and mouse genetics approaches to test whether Myh14 deficiency leads to alteration in hypertrophic, Wnt/?-catenin and FOXO1 signaling. The proposed research will provide fundamental insights into how Myh14 modulates stress-induced cardiac remodeling and open a new understanding of how common genetic variation plays a role in stress-induced cardiac remodeling. The outlined program will allow the candidate to develop a mastery in the functional validation of novel candidate genes in cardiac remodeling using molecular biology, cell biology and mouse genetics techniques towards the long-term goal of understanding how genetic variation modifies cardiovascular disease in humans. The intensive research plan will allow the candidate to embark upon this research project, while having the necessary mentorship and support needed towards the goal of maturing into an independent investigator. The aims of this project are aligned with the major strategic goal of NIH and NHLBI to improve our understanding of the molecular and physiologic basis of health and disease.